Anti-apoptotic signaling by the interleukin-2 receptor reveals a function for cytoplasmic tyrosine residues within the common gamma (gamma c) receptor subunit

The interleukin-2 receptor (IL-2R) is composed of one affinity-modulating subunit (IL-2Ralpha) and two essential signaling subunits (IL-2Rbeta and gammac). Although most known signaling events are mediated through tyrosine residues located within IL-2Rbeta, no functions have yet been ascribed to gammac tyrosine residues. In this study, we describe a role for gammac tyrosines in anti-apoptotic signal transduction. We have shown previously that a tyrosine-deficient IL-2Rbeta chain paired with wild type gammac stimulated enhancement of bcl-2 mRNA in IL-2-dependent T cells, but it was not determined which region of the IL-2R or which pathway was activated to direct this signaling response. Here we show that up-regulation of Bcl-2 by an IL-2R lacking IL-2Rbeta tyrosine residues leads to increased cell survival after cytokine deprivation; strikingly, this survival signal does not occur in the absence of gammac tyrosine residues. These gammac-dependent signals are revealed only in the absence of IL-2Rbeta tyrosines, indicating that the IL-2R engages at least two distinct signaling pathways to regulate apoptosis and Bcl-2 expression. Mechanistically, the gammac-dependent signal requires activation of Janus kinases 1 and 3 and is sensitive to wortmannin, implicating phosphatidylinositol 3-kinase. Consistent with involvement of phosphatidylinositol 3-kinase, Akt can be activated via tyrosine residues on gammac. Thus, gammac mediates an anti-apoptotic signaling pathway through Akt which cooperates with signals from its partner chain, IL-2Rbeta

Unique MicroRNA Expression Profiles in Cervical Cancer.

Cervical cancer is the second leading cause of death among female patients with cancer in the world. Our aim was to analyze cervical cancer cases, in the Southwestern Transdanubian Region of Hungary, with regard to human papillomavirus (HPV) genotype and histological and clinical grading. After HPV testing and genotyping, the expressions of eight different pre-microRNAs (miR-21, miR-27a, miR-34a, miR-146a, miR-155, miR-196a, miR-203, miR-221) in formalin-fixed paraffin-embedded (FFPE) primary human cervical cancer samples were evaluated with the help of the LightCycler 480 PCR System (Roche). Statistically significant overexpression of miR-21 (p=0.004), miR-27a (p=0.018), miR-34a (p<0.001), miR-155 (p=0.021), miR-196a (p=0.032), miR-203 (p=0.037) and miR-221 (p=0.017) were observed in squamous cell carcinoma, regardless of HPV status and clinical grading. Significant overexpression of miR-21 (p=0.004), miR-27a (p=0.02), miR-34a (p<0.001), miR-196a (p=0.027) and miR-221 (p=0.031) was characteristic of HPV-positive squamous cell carcinomas in contrast to adenocarcinomas of the same HPV status

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The interleukin (IL)-2 family cytokines: Survival and proliferation signaling pathways in T lymphocytes

Lymphocyte populations in the immune system are maintained by a well-organized balance between cellular proliferation, cellular survival and programmed cell death (apoptosis). One of the primary functions of many cytokines is to coordinate these processes. In particular, the interleukin (IL)-2 family of cytokines, which consists of six cytokines (IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21) that all share a common receptor subunit (gammac), plays a major role in promoting and maintaining T lymphocyte populations. The details of the molecular signaling pathways mediated by these cytokines have not been fully elucidated. However, the three major pathways clearly involved include the JAK/STAT, MAPK and phosphatidylinositol 3-kinase (PI3K) pathways. The details of these pathways as they apply to the IL-2 family of cytokines is discussed, with a focus on their roles in proliferation and survival signaling

Human papillomavirus detection and genotyping, by HC2, full-spectrum HPV and molecular beacon real-time HPV assay in an Irish colposcopy clinic

Cervical screening programmes are moving towards HPV testing as part of the screening process and as a triage for colposcopy. Three HPV detection methods were evaluated using cervical cytology specimens from colposcopy patients. PreservCyt liquid based cytology specimens from 241 women attending colposcopy clinics with greater than 2 persistently abnormal smears were recruited through the Coombe Women and Infants University Hospital, Dublin. HPV DNA was detected by Hybrid Capture (HC2) for 13 high-risk HPV types, Full-Spectrum HPV (FS-HPV) for 49 high and low-risk types and Molecular Beacon Real-Time HPV assay (MBRT-HPV) for 16 high and low-risk types. HPV genotyping was performed using Linear Array HPV Assay (LA-HPV). HPV was detected in 83.3% (195/234), 91.9% (217/236) and 80.1% (169/211) of cytology specimens by HC2, FS-HPV and MBRT-HPV, HPV DNA detection assays. The sensitivity of the assays for the detection of high-risk HPV in cytology specimens that had a Cervical Intraepithelial Neoplasia Grade 2+ result by histology were, 98%, 97% and 94% for HC2, FS-HPV and MBRT-HPV assays with positive predictive values of 94.1%, 94.1% and 97.3%. The most common HPV genotypes were HPV 16, 31, 33, 58, 42, 61 and 53, and the most common high-risk HPV genotypes were HPV 16, 31, 33, 58, 18, 45, 59, 51, 56 and 39, with detection of multiple infections in 57.7% of all cases. FS-HPV and MBRT-HPV are highly sensitive and have a similarly high PPV as the HC2 assay for detection of HPV in patients with Cervical Intraepithelial Neoplasia Grade 2+ disease. HPV genotyping of women with persistent abnormalities is warranted prior to the introduction of HPV DNA testing in a colposcopy setting

Dual-Stained Cervical Cytology and Histology with Claudin-1 and Ki67

Several biomarkers are in use to improve the sensitivity and specificity of cervical cancer screening. Previously, increased expression of tight junction protein claudin-1 (CLDN1) was detected in premalignant and malignant cervical lesions and applied for cytology screening. To improve the specificity, a double immunoreaction with CLDN1/Ki67 was developed in the recent study. Parallel p16/Ki67 (CINtec(R) PLUS) and CLDN1/Ki67 dual-stained cytology and histology were performed and compared. p16/Ki67 immunoreaction showed positivity in 317 out of 1596 smears with negativity in 1072 and unacceptable reactions in 207 samples. CLDN1/Ki67 dual staining was positive in 200 of 1358 samples, negative in 962, whereas 196 smears could not be evaluated due to technical reasons. Considering the high-grade squamous intraepithelial lesion cytology as gold standard, sensitivity of CLDN1/Ki67 reaction was 76%, specificity was 85.67%, while for p16/Ki67 sensitivity was 74% and specificity was 81.38%. Comparison of CLDN1/Ki67 and p16/Ki67 dual stainings showed the results of the two tests not to be significantly different. Analysing histological slides from 63 cases, the results of the two tests agreed perfectly. As conclusion the sensitivity and specificity proved to be similar using p16/Ki67 and CLDN1/Ki67 double immunoreactions both on LBC samples and on histological slides